1. State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China;
2. College of Material Science and Chemical Engineering, Tianjin University of Science and Technology, Tianjin 300457, P. R. China;
3. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P. R. China;
4. International Medicine Center, Tianjin Hospital, Tianjin 300457, P. R. China.
* These authors contributed equally to this work.
Phthalocyanines (Pcs) are a group of promising photosensitizers for use in photodynamic therapy (PDT). However, their extremely low solubility and their strong tendency to aggregate in aqueous solution greatly restrict their application. Conjugation of Pc macrocycles with peptide ligands could be a very useful strategy to optimize the physical properties of Pcs not only by increasing their water solubility and reducing their aggregation but also by endowing the conjugates with a tumor-targeting capability. To develop highly potent photosensitizers for tumor PDT, we prepared new peptide-conjugated photosensitizers using silicon Pc (SiPc), which has much higher photodynamic activity than zinc Pcs, as the light activation moiety and the cRGDfK peptide (or simply cRGD) as the peptide moiety. A polyethylene glycol linker and an extra carboxylic acid group were also tested for introduction into the conjugates to optimize the conjugate structure. The conjugates' photophysical and photodynamic behaviors were then carefully evaluated and compared using in vitro and in vivo experiments. One of the prepared conjugates, RGD-(Linker)2-Glu-SiPc, showed excellent physical properties and photodynamic activity, with an EC50 (half maximal effective concentration) of 10-20 nM toward various cancer cells. This conjugate eradicated human glioblastoma U87-MG tumors in a xenograft murine tumor model after only one dose of photodynamic treatment, with no tumor regrowth during observation for up to 35 days. The conjugate RGD-(Linker)2-Glu-SiPc thus showed highly promising potential for use in tumor treatment.
Keywords: photodynamic therapy, silicon phthalocyanine, integrin, photosensitizer, peptide conjugate.